Introduction To Toxicology - European Commission
ToxicologyTRAINING FOR THE HEALTH SECTORIntroduction to ToxicologyChildren's Health and the EnvironmentCHEST Training Package for the Health Sector NOTE TO USER: Please add details of the date, time, place andsponsorship of the meeting for which you are using thispresentation. 1
ToxicologyDefinition ToxicologyDefinition of toxicology is "the study of theadverse effects of chemicals or physicalagents on living organismsThe traditional definition of toxicology is "the science ofpoisons." As our understanding of how various agents can causeharm to humans and other organisms, a more descriptive definition oftoxicology is "the study of the adverse effects of chemicals or physicalagents on living organisms".Adverse effects may occur in many forms, ranging from immediatedeath to subtle changes not realized until months or years later. Theymay occur at various levels within the body, such as an organ, a type ofcell, or a specific biochemical. Knowledge of how toxic agents damagethe body has progressed along with medical knowledge. It is nowknown that various observable changes in anatomy or body functionsactually result from previously unrecognized changes in specificbiochemicals in the body.The textbooks listed below are quite comprehensive and widely used inbasic toxicology training courses.Casarett and Doull's Toxicology (C. Klaassen, M. Amdur, and J.Doull, eds.)Principles and Methods of Toxicology (A. W. Hayes, ed.)Basic Environmental Toxicology (L. Cockerham and B. Shane, eds.)2
ToxicologyPhilippus Theophrastus AureolusBombastus von HohenheimPARACELSUS(Einsiedeln, Zürich, 1493 Salzburg, 1541)All substances are poisons; it is the dose that makes the poisonThe historical development of toxicology began with early cave dwellers who recognizedpoisonous plants and animals and used their extracts for hunting or in warfare. By 1500 BC,written recordings indicated that hemlock, opium, arrow poisons, and certain metals wereused to poison enemies or for state executions.With time, poisons became widely used and with great sophistication. Notable poisoningvictims include Socrates, Cleopatra, and Claudius. By the time of the Renaissance and Ageof Enlightenment, certain concepts fundamental to toxicology began to take shape. Thestudies of Paracelsus ( 1500AD) and Orfila ( 1800 AD) are well known.Paracelsus determined that specific chemicals were actually responsible for the toxicity of aplant or animal poison. He also documented that the body's response to those chemicalsdepended on the dose received. His studies revealed that small doses of a substance mightbe harmless or beneficial whereas larger doses could be toxic. This is now known as thedose-response relationship, a major concept of toxicology. Paracelsus was one of thefounders of modern toxicology. His best known quote: All substances are poisons; it is thedose that makes the poison.Orfila, a Spanish physician, is often referred to as the founder of toxicology. It was Orfilawho first prepared a systematic correlation between the chemical and biological properties ofpoisons of the time. He demonstrated effects of poisons on specific organs by analyzingautopsy materials for poisons and their associated tissue damage.The 20th century is marked by an advanced level of understanding of toxicology. DNA (themolecule of life) and various biochemicals that maintain body functions werediscovered. Our level of knowledge of toxic effects on organs and cells is now beingrevealed at the molecular level. It is recognized that virtually all toxic effects are caused bychanges in specific cellular molecules and biochemicals.Xenobiotic is the general term that is used for a foreign substance taken into the body. It isderived from the Greek term xeno which means "foreigner." Xenobiotics may producebeneficial effects (such as a pharmaceuticals) or they may be toxic (such as lead).As Paracelsus proposed centuries ago, dose differentiates whether a substance will be aremedy or a poison. A xenobiotic in small amounts may be non-toxic and even beneficial butwhen the dose is increased, toxic and lethal effects may result.3
ToxicologyToxicology TerminologyToxicology is the study of the adverse effects of chemicals or physical agents on livingorganisms. A toxicologist is a scientist that determines the harmful effects of agentsand the cellular, biochemical, and molecular mechanisms responsible for the effects.Toxicant, toxin, and poison are often used interchangeably in the literature; however,there are subtle differences as indicated in the table.Toxic substances may be systemic toxins or organ toxins.A systemic toxin is one that affects the entire body or many organs rather than aspecific site. For example, potassium cyanide is a systemic toxicant in that it affectsvirtually every cell and organ in the body by interfering with the cell's ability to utilizeoxygen.Toxicants may also affect only specific tissues or organs while not producing damage tothe body as a whole. These specific sites are known as the target organs or targettissues.Some examples: Benzene is a specific organ toxin in that it is primarily toxic to theblood-forming tissues.Lead is also a specific organ toxin; however, it has three target organs (central nervoussystem, kidney, and hematopoietic system).4
ToxicologyToxic agent or substanceToxic agent is anything that can producean adverse biological effect. It may bechemical, physical, or biological in form.Toxic agents may be:chemical (such as cyanide),physical (such as radiation) andbiological (such as snake venom).Toxic substance is simply a material whichhas toxic properties.A toxic agent is anything that can produce an adverse biological effect. It may be chemical, physical,or biological in form. For example, toxic agents may be chemical (such as cyanide), physical (such asradiation) and biological (such as snake venom).A distinction is made for diseases due to biological organisms. Those organisms that invade andmultiply within the organism and produce their effects by biological activity are not classified as toxicagents. An example of this is a virus that damages cell membranes resulting in cell death.If the invading organisms excrete chemicals which is the basis for toxicity, the excreted substances areknown as biological toxins. The organisms in this case are referred to as toxic organisms. Anexample is tetanus. Tetanus is caused by a bacterium, Clostridium tetani. The bacteria C. tetani itselfdoes not cause disease by invading and destroying cells. Rather, it is a toxin that is excreted by thebacteria that travels to the nervous system (a neurotoxin) that produces the disease.A toxic substance is simply a material which has toxic properties. It may be a discrete toxic chemicalor a mixture of toxic chemicals. For example, lead chromate, asbestos, and gasoline are all toxicsubstances. Lead chromate is a discrete toxic chemical. Asbestos is a toxic material that does notconsist of an exact chemical composition but a variety of fibers and minerals. Gasoline is also a toxicsubstance rather than a toxic chemical in that it contains a mixture of many chemicals. Toxicsubstances may not always have a constant composition. For example, the composition of gasolinevaries with octane level, manufacturer, time of season, etc.oxic substances may be organic or inorganic in composition5
ToxicologySystematic or organ toxins A systemic toxin is one that affects theentire body or many organs rather than aspecific site A organ toxin is one that affects onlyspecific tissues or organsToxic substances may be systemic toxins or organ toxins.A systemic toxin is one that affects the entire body or many organs rather than a specific site. Forexample, potassium cyanide is a systemic toxicant in that it affects virtually every cell and organ inthe body by interfering with the cell's ability to utilize oxygen.Toxicants may also affect only specific tissues or organs while not producing damage to the bodyas a whole. These specific sites are known as the target organs or target tissues.Examples: Benzene is a specific organ toxin in that it is primarily toxic to the blood-formingtissues.Lead is also a specific organ toxin; however, it has three target organs (central nervous system,kidney, and hematopoietic system).A toxicant may affect a specific type of tissue (such as connective tissue) that is present in severalorgans. The toxic site is then referred to as the target tissue.There are many types of cells in the body and they can be classified in several ways.basic structure (e.g., cuboidal cells)tissue type (e.g., hepatocytes of the liver)germinal cells (e.g., ova and sperm)somatic cells (e.g., non-reproductive cells of the body)Germ cells are those cells that are involved in the reproductive process and can give rise to a neworganism. They have only a single set of chromosomes peculiar to a specific sex. Male germ cellsgive rise to sperm and female germ cells develop into ova. Toxicity to germ cells can cause effectson the developing fetus (such as birth defects, abortions).Somatic cells are all body cells except the reproductive germ cells. They have two sets (or pairs)of chromosomes. Toxicity to somatic cells causes a variety of toxic effects to the exposedindividual (such as dermatitis, death, and cancer).6
ToxicologyFactors determining adverse effects intrinsic toxicity dose exposure conditions response of hostSeveral factors will be discussed determining the adverse effects oftoxic agents.7
ToxicologyIntrinsic toxicity Chemical propertiesmolecular structure & functional groupssolubility - insolubilityvolatilitystability (light, water, acids, enzymes, )reactivity Physical propertiesgas (density, )liquid (vapour pressure, )solid (crystal structure, size, shape, )Information on chemical properties and physical properties of toxicagents can be found at several websites.Material Safety Data Sheets are available for most chemicals. USEnvironmental Protection Agency has a site called IRIS with plenty ofdata on chemical properties.Stability means that some compounds might change under influence oflight, water, acids or other external factors.The same data sheets have information about the physical properties ofchemicals.8
ToxicologyMisunderstandings Natural compounds safe compounds Synthetic agents toxic agents Pure substance pure substance impurities pure substance in (complex) mixtureThese are some reminders about common misunderstandings.Sometimes there is confusion about the terminology related tocompounds.9
ToxicologyFactors determining adverse effects intrinsic toxicity dose exposure conditions response of hostThe second factor determining adverse efects is the dose.10
ToxicologyDoseThe dose is the amount of a substanceadministered at one timeDose by definition is the amount of a substance administered at onetime. However, other parameters are needed to characterize theexposure to xenobiotics. The most important are the number of doses,frequency, and total time period of the treatment.Some examples:500 mg Asperin as a single dose500 mg Penicillin every 8 hours for 10 days15 mg DDT per day for 60 days11
ToxicologyDoseTypes of doses, e.g., exposure dose,absorbed dose, administered dose andtotal doseThere are numerous types of doses, e.g., exposure dose, absorbeddose, administered dose and total dose.Fractionating a total dose usually decreases the probability that thetotal dose will cause toxicity. The reason for this is that the body oftencan repair the effect of each subtoxic dose if sufficient time passesbefore receiving the next dose. In such a case, the total dose, harmfulif received all at once, is non-toxic when administered over a period oftime. For example, 30 mg of strychnine swallowed at one time could befatal to an adult whereas 3 mg of strychnine swallowed each day for tendays would not be fatal.12
ToxicologyDose unitsThe units used in toxicology are basically the same as those used in medicine. The gram is thestandard unit. However, most exposures will be smaller quantities and thus the milligram (mg) iscommonly used. For example, the common adult dose of Tylenol is 650 milligrams.The clinical and toxic effects of a dose must be related to age and body size. For example, 650 mgis the adult dose of Tylenol. That would be quite toxic to young children, and thus Children's Tylenoltablets contain only 80 mg. A better means to allow for comparison of effectiveness and toxicity isthe amount of a substance administered on a body weight basis. A common dose measurement ismg/kg which stands for mg of substance per kg of body weight.Another important aspect is the time over which the dose is administered. This is especiallyimportant for exposures of several days or for chronic exposures. The commonly used time unit isone day and thus, the usual dosage unit is mg/kg/day.Since some xenobiotics are toxic in much smaller quantities than the milligram, smaller fractions ofthe gram are used, such as microgram (µg). Other units are shown in the slide.In the environmental sciences Environmental exposure units are expressed as the amount of axenobiotic in a unit of the media.mg/liter (mg/l) for liquidsmg/gram (mg/g) for solidsmg/cubic meter (mg/m3) for airSmaller units are used as needed, e.g., µg/ml.Other commonly used dose units for substances in media are parts per million (ppm), parts perbillion (ppb) and parts per trillion (ppt).The dose level at which a toxic effect is first encountered is known as the threshold dose. Dosesbelow the threshold dose are often referred to as "subthreshold doses."13
ToxicologyDose-response relationship“The dose-response relationship is themost fundamental and pervasiveconcept in toxicology”The dose-response relationship is a fundamental and essential conceptin toxicology. It correlates exposures and the spectrum of inducedeffects. Generally, the higher the dose, the more severe theresponse. The dose-response relationship is based on observed datafrom experimental animal, human clinical, or cell studies.14
ToxicologyDose-effect relationshipKnowledge of the dose-response relationship:- establishes causality that the chemical has in fact induced theobserved effects- establishes the lowest dose where an induced effect occurs - thethreshold effect- determines the rate at which injury builds up - the slope for the doseresponse.Within a population, the majority of responses to a toxicant are similar;however, a wide variance of responses may be encountered, someindividuals are susceptible and others resistant. As demonstratedabove, a graph of the individual responses can be depicted as a bellshaped standard distribution curve.Dose responses are commonly presented as mean 1 S.D. (standarddeviation), which incorporates 68% of the individuals. The variancemay also be presented as two standard deviations, which incorporates95% of the responses. A large standard deviation indicates greatvariability of response. For example, a response of 12 5 mg indicatesconsiderably more variability than 12 1 mg.15
ToxicologyDose-response curveThe dose-response curve normally takes the form of a sigmoid curve. Itconforms to a smooth curve as close as possible to the individual datapoints. For most effects, small doses are not toxic. The point at whichtoxicity first appears is known as the threshold dose level. From thatpoint, the curve increases with higher dose levels. In the hypotheticalcurve above, no toxicity occurs at 10 mg whereas at 35 mg 100% of theindividuals experience toxic effects.There is always a relation between dose and effect/response, but forsome agents there is a threshold below which no effect occurs.A threshold for toxic effects occurs at the point where the body's abilityto detoxify a xenobiotic or repair toxic injury has been exceeded. Formost organs there is a reserve capacity so that loss of some organfunction does not cause decreased performance. For example, thedevelopment of cirrhosis in the liver may not result in a clinical effectuntil over 50% of the liver has been replaced by fibrous tissue.16
ToxicologyDose-response curveKnowledge of the shape and slope of the dose-response curve isextremely important in predicting the toxicity of a substance at specificdose levels. Major differences among toxicants may exist not only inthe point at which the threshold is reached but also in the percent ofpopulation responding per unit change in dose (i.e., the slope). Asillustrated above, Toxicant A has a higher threshold but a steeper slopethan Toxicant B.Knowledge of the dose-response relationship permits one to determinewhether exposure has caused an effect, threshold for the effect, and therate of buildup of the effect with increasing dose levels. Rate of buildupof toxic effects is known as the "slope" of the dose-response curve.17
ToxicologyDose estimatesDose Estimates of Toxic EffectsDose-response curves are used to derive dose estimates of chemicalsubstances. A common dose estimate for acute toxicity is the LD50(Lethal Dose 50%). This is a statistically derived dose at which 50% ofthe individuals will be expected to die. The figure illustrates how anLD50 of 20 mg is derived.Other dose estimates also may be used. LD0 represents the dose atwhich no individuals are expected to die. This is just below thethreshold for lethality. LD10 refers to the dose at which 10% of theindividuals will die.For inhalation toxicity, air concentrations are used for exposurevalues. Thus, the LC50 is utilized which stands for LethalConcentration 50%, the calculated concentration of a gas lethal to 50%of a group. Occasionally LC0 and LC10 are also used.18
ToxicologyEffective doseEffective Doses (EDs) are used to indicate the effectiveness of asubstance. Normally, effective dose refers to a beneficial effect (reliefof pain). It might also stand for a harmful effect. Thus the specificendpoint must be indicated.19
ToxicologyToxic doseToxic Doses (TDs) are utilized to indicate doses that cause adversetoxic effects. The usual dose estimates are seen in the table.The knowledge of the effective and toxic dose levels aides thetoxicologist and clinician in determining the relative safety of toxicagents. Two dose-response curves can be presented for the samedrug, one for effectiveness and the other for toxicity. In this case, adose that is 50-75% effective does not cause toxicity whereas a 90%effective dose may result in a small amount of toxicity.20
ToxicologyThe toxic dose is seen at an increasing dose compared with theeffective dose. As can been seen in the graph, it is ppossible to have anoverlap of having an effective dose while this is also starting to be toxic.Question: The quantity of a substance administered to an individualover a period of time or in several individual doses is known as the:O Exposure DoseO Absorbed DoseO Total DoseAnswer: The total dose is the quantity of a substance administered toan individual over a period of time or in several individual doses. Itbecomes particularly important when evaluating cumulative poisons.21
ToxicologyNOAEL and LOAELTwo terms often encountered are No Observed Adverse Effect Level(NOAEL) and Low Observed Adverse Effect Level (LOAEL). Theyare the actual data points from human clinical or experimental animalstudies.Sometimes the terms No Observed Effect Level (NOEL) and LowestObserved Effect Level (LOEL) may also be found in theliterature. NOELs and LOELs do not necessarily imply toxic or harmfuleffects and may be used to describe beneficial effects of chemicals aswell.The NOAEL, LOAEL, NOEL, and LOEL have great importance in theconduct of risk assessments.22
ToxicologyDose-response relationshipOur knowledge of the effects of chemicalsstems mainly from clinical and occupational toxicology relatively high doses, limited number of agents epidemiology complex exposures, rarely “causal” associations animal experiment
4 Toxicology Toxicology Terminology Toxicology is the study of the adverse effects of chemicals or physical agents on living organisms. A toxicologist is a scientist that determines the harmful effects of agents and the cellular, biochemical, and molecular mechanisms responsible for the effects. Toxicant, toxin, and poison are often used interchangeably in the literature; however,
CONCEPTS. MARINA GOUMENOU Chemist - Toxicologist BSc, MSc, PhD, ERT EUROPEAN FOOD SAFETY AUTHORITY . represent an official view of European Food Safety Authority Dr. Marina, Goumenou, Scope and ethical principles of toxicology and 3R, EUROTOX Course of Basic Toxicology, Zagreb, Croatioa, 4/4/2016 . Introduction to Toxicology, the Dose .
toxicology data would potentially be required. For example, as noted in the toxicology data requirements table, swimming pool, wood preservative, metalworking fluid, and aquatic areas uses require toxicology data in addition to the core toxicology data. Again, the use pattern and specific use site(s) should be examined to determine the data .
A Small Dose of Toxicology A book chapter of A Small Dose of Toxicology - The Health Effects of Common Chemicals By Steven G. Gilbert, PhD, DABT Institute of Neurotoxicology & Neurological Disorders (INND) Seattle, WA 98115 E-mail: sgilbert@innd.org Supporting web sites web: www.asmalldoseof.org - "A Small Dose of Toxicology"
Toxicology Tutors (Tox Tutors) In the Tox Tutors , created by the US Health and Human Services, you can learn about the history and explore an introduction to the basic principles of toxicology in the module entitled Introduction to Toxicology and Dose-Response.
forensic toxicology). SWGTOX will also establish a uniform Code of Ethics for forensic toxicologists, identify areas of research and development in the field of forensic toxicology, and promote public awareness of the field of forensic toxicology through outreach. What professional groups
The classic connotation of toxicology was "the science of poisons." Since that time, the science has expanded to encompass several disciplines. Toxicology is the study of the interaction between chemical agents and biological systems. While the subject of toxicology is quite complex, it is necessary to understand the basic concepts in order to make
toxicology and carcinogenesis studies were conducted in F344/N rats by administering hexachloro- ethane (approximately 99%pure) in corn oil by gavage to groups of males and females for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chi- nese hamster ovary (CHO) cells.
Animal nutrition, life stage, diet, breed-specific, neutered AVAST array of life-stage diets are available, and these can be subdivided to encompass neutered pet diets, breed-specific diets and those with different requirements (whether a mobility or hairball diet). So, do pets require these different life-stage diets, or is it all a marketing ploy by nutrition companies? Selecting the right .
